1. We have explored the hitherto unexplained enhancement of the anti-HIV activity and the 5'-phosphorylation of 2',3'-dideoxypurine nucleosides by inosine monophosphate dehydrogenase (IMPD) inhibitors such as ribavirin, tiazofurin and mycophenolic acid. The latter agents, although themselves without anti-HIV activity, can stimulate the anti-HIV activity of ddi or ddG as much as 4-fold in appropriate assay systems. The enhancement appears to be due to an increased concentration of IMP arising as a consequence of IMPD inhibition by these agents, with IMP acting as the phosphate donor for the initial phosphorylation of ddl or ddg to ddIMP and ddGMP. Of the combinations examined, ddi/ribavirin may have the greatest potential for clinical use since both of these agents are in active clinical trial at the present time (ddI as an anti-HIV agent, and ribavirin in the treatment of other virus infections). 2. In view of the activity of 2',3'- dideoxynucleosides as anti-hepatitis B virus (HBV) agents, we have explored the activation of these agents in the isolated hepatocyte system. Unlike the relationship seen in the HIV system, the activity of these agents against HBV did not correlate with their efficiency of phosphorylation. ddG, for example, is phosphorylated relatively slowly, but is the most active of these agents against HBV. It appears likely that specificity is conferred by the dG termination of the negative strand of HBV, rendering this virus specifically sensitive to ddG analogues. 3. The pharmacology of cyclopentenyl cytosine (CPEC) (NSC 375575) has been explored extensively. The compound appears to act primarily via inhibition of CTP synthetase by its anabolite CPEC-TP. Cytidine effectively reverses the toxicity of the drug, even when administered several hours after CPEC. CPEC is scheduled for Phase I clinical trial in the fall of 1991.